Angiopreventive versus angiopromoting effects of allopurinol in the murine sponge model

• Published in: Microvascular research 2015-09, Vol.101, p.118-126
• Main Authors: Orellano, L.A.A., Almeida, S.A., Campos, P.P., Andrade, S.P.
• Format: Article
• Language: English
• Subjects: Acetylglucosaminidase - metabolism; Allopurinol; Allopurinol - chemistry; Angiogenesis; Animals; Collagen - chemistry; Ether - chemistry; Hemoglobins - analysis; Hemoglobins - metabolism; Hydrogen Peroxide - chemistry; Inflammation; Male; Mice; Mice, Inbred C57BL; Models, Animal; Neovascularization, Pathologic - drug therapy; Nitric Oxide - chemistry; Peroxidase - metabolism; Polyurethanes - chemistry; Sponge implant; Time Factors; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Vascular Endothelial Growth Factor A - metabolism; Xanthine Oxidase - antagonists & inhibitors
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2015.07.003

Recent data has indicated that, besides its classical therapeutic indication in hyperurecemia and gout, xanthine oxidase inhibitors can be used to various forms of ischemia and other types of tissue and vascular injuries. We tested the hypothesis that allopurinol, an inhibitor of xanthine oxidase (XO), might modulate acute and/or chronic inflammatory angiogenesis induced by subcutaneous implantation of synthetic matrix in mice. C57/BL6 male mice (6–7 weeks) were implanted with polyether–polyurethane sponge discs. The animals received by oral gavage 1.0mg/kg of allopurinol for six consecutive days in two treatment regimen. In the first series of experiments, the treatment was initiated 24h post-implantation and the implants were removed at day 7 post-implantation. For the assessment of the effect of the compound on chronic inflammation, the treatment was initiated at day 8 post-implantation and the implants removed 14days post-implantation. Angiogenesis as determined by hemoglobin content, VEGF levels and number of vessels intraimplant, and inflammation (myeloperoxidase —MPO, n-acetyl-β-d-glucosaminidase —NAG, TNF-α and CCL2 levels) were reduced by allopurinol treatment in acute phase. Similarly, the treatment inhibited nitric oxide and H2O2 production. However, fibrogenesis determined by collagen deposition and levels of TGF-β1 increased in the implants after allopurinol treatment. In marked contrast with the effects when the treatment initiated 24h post-implantation, allopurinol increased angiogenesis and inflammation but reduced collagen and TGF-β1 levels intra-implant, when the treatment was started during the chronic inflammatory process. The dual effects of allopurinol described here, extend its range of actions as a potential agent able to modulate the components of the fibrovascular tissue present in both physiological (healing processes) as well as in chronic fibroproliferative diseases. These modulatory effects depended on the phase at which the treatment was initiated. •Allopurinol exerts dual effects on fibrovascular tissue.•Inflammation and angiogenesis are inhibited by allopurinol if treatment starts soon after injury.•Allopurinol possesses both pro-healing and anti-fibrogenic effects.